Version May 2024
INTRODUCTION — The polymyxins comprise a separate class of antibiotics and include a number of different compounds. However, only polymyxin B and polymyxin E (also known as colistin) are in clinical use [1]. They were isolated from Paenibacillus polymyxa and became available for clinical use in the 1950s [2,3]. Colistin was historically given as an intramuscular injection for the treatment of gram-negative bacterial infections, but fell out of favor after aminoglycosides became available because of its significant side effects, particularly nephrotoxicity.
More recently, intravenous polymyxin B and colistin have been used more frequently in the treatment of otherwise panresistant nosocomial infections, especially those due to Pseudomonas and Acinetobacter spp [4-8]. They are also used in aerosolized form for patients with cystic fibrosis. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)
Polymyxin B and colistin have almost identical chemical structures and comparable mechanisms of action, resistance patterns, and spectra of activity. However, they have very different pharmacokinetics and pharmacodynamics [9]. These will all be reviewed here along with their adverse effects. The clinical settings in which the polymyxins may be used are discussed separately in the appropriate topic reviews.
MECHANISM OF ACTION — Polymyxins are bactericidal drugs that bind to lipopolysaccharides (LPS) and phospholipids in the outer cell membrane of gram-negative bacteria. They competitively displace divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents, and bacterial death [3,10,11].
In addition to their bactericidal effect, the polymyxins can bind and neutralize LPS and may reduce the pathophysiologic effects of endotoxin in the circulation [12,13].
SPECTRUM OF ACTIVITY — Polymyxins have a narrow antibacterial spectrum limited to a subset of gram-negative bacilli. They are primarily used for infections due to multidrug-resistant organisms, such as carbapenem-resistant Enterobacterales (eg, Escherichia coli, Klebsiella pneumoniae, some Enterobacter spp), Pseudomonas aeruginosa, and Acinetobacter baumannii. Other susceptible organisms include Haemophilus influenzae, Bordetella pertussis, Legionella pneumophila, Salmonella spp, Shigella spp, and the majority of Stenotrophomonas maltophilia strains (74 percent of 23 tested isolates in one report) [14].
On the other hand, Burkholderia cepacia, Serratia marcescens, Moraxella catarrhalis, Proteus spp, Providencia spp, and Morganella morganii are all resistant to polymyxins. Other inherently resistant organisms include all gram-positive bacteria and gram-negative cocci.
Organisms with variable resistance include Aeromonas, Vibrio, Prevotella, and Fusobacterium spp [3,15,16].
RESISTANCE
Prevalence and mechanisms — Resistance to the polymyxins is rare, although there have been increasing reports of polymyxin resistance among carbapenem-resistant gram-negative bacilli [17-20]. Furthermore, the identification of plasmid-mediated resistance to the polymyxins via the mcr-1 gene raises concern for continued widespread dissemination of resistance [21].
The mechanisms of polymyxin resistance remain the subject of ongoing research, although a common mechanism appears to be modification of the lipid A component of lipopolysaccharide (LPS). Other mechanisms may include cessation of LPS production or activation of efflux pumps [22]. Heteroresistance to colistin has been demonstrated in vitro [23,24].
Plasmid-mediated resistance to the polymyxins due to an enzyme that modifies lipid A (a phosphoethanolamine transferase) and can be transferred in vitro to other bacterial genera has also been described, prompting concerns that polymyxin resistance could become more widespread. In a study from China, a plasmid gene associated with in vitro colistin resistance (mcr-1) was first identified through surveillance of E. coli isolated from food animals, and in 2014, was identified in 16 of 1322 clinical isolates (1.2 percent) from hospitalized patients with Enterobacteriaceae infections [25]. This resistance mechanism has subsequently been reported across the globe [22,26-28].
Polymyxins have been used in veterinary medicine for many years, raising the question of transmission of resistant isolates to humans from animal sources. There have been efforts over recent years to reduce veterinary use of these agents [29].
Susceptibility testing — For colistin susceptibility testing, broth microdilution is the method recommended by both the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the American Clinical and Laboratory Standards Institute (CLSI). Other methods (eg, E-test, agar dilution, disc diffusion, Sensititre, and Vitek-2) do not appear to be as reliable [30-35].
The 2020 version of CLSI [36] and the 2022 version of EUCAST [37] have updated susceptibility breakpoints for the polymyxins and differ in their recommendations.
The CLSI-recommended breakpoints for colistin and polymyxin B for Enterobacterales, P. aeruginosa, and Acinetobacter species are:
●MIC ≤2 mcg/mL: Intermediate
●MIC ≥4 mcg/mL: Resistant
The EUCAST-recommended breakpoints for colistin for Enterobacterales and P. aeruginosa are [37]:
●MIC ≤2 mg/L: Susceptible
●MIC >2 mg/L: Resistant
The EUCAST-recommended breakpoints for colistin for Acinetobacter species are:
●MIC ≤4 mg/L: Susceptible
●MIC >4 mg/L: Resistant
PHARMACOKINETICS
Polymyxin B — Polymyxin B is given intravenously as polymyxin B sulfate, the active form. Pharmacokinetic data on polymyxin B are very limited. Most (>95 percent) of it is cleared independently of the kidney. Little is known about its extravascular distribution or penetration into other tissues [9], but it is thought to be similar to that of colistin, with generally poor penetration into the lungs, pleura, bones, and central nervous system.
Polymyxin B is not absorbed from the gastrointestinal tract. Topical, nonabsorbable oral, and ophthalmic formulations are available. Other routes of administration include inhaled and intrathecal administration. (See 'Inhaled administration' below and 'Intrathecal administration' below.)
Colistin — Colistin is available as both colistin sulfate and colistimethate sodium (CMS). Neither form is absorbed from the gastrointestinal tract. Colistin sulfate is formulated only as topical and nonabsorbable oral products. CMS is a prodrug that is hydrolyzed after intravenous or inhaled administration to produce several derivatives, including the active drug colistin.
Colistin is tightly bound to membrane lipids of cells of many body tissues, including the liver, lung, kidney, brain, heart, and muscles [38]. Data on the pharmacokinetics of intravenous CMS are sparse [39,40]. CMS has a half-life of 124 minutes, whereas colistin (base) has a half-life of 251 minutes [40]. Colistin has a calculated volume of distribution of 0.34 L/kg [40]. CMS is excreted in the urine, and colistin is non-renally excreted. No biliary excretion has been reported in humans.
The distribution of colistin to the pleural cavity, lung parenchyma, bones, and cerebrospinal fluid (CSF) is relatively poor [41,42]. Colistin CSF penetration is low (CSF-to-serum ratio of 5 percent), and bactericidal concentrations are not achieved [43].
Other routes of administration include inhaled and intrathecal administration. (See 'Inhaled administration' below and 'Intrathecal administration' below.)
DOSING AND ADMINISTRATION — An international expert group of clinicians and pharmacists has released consensus guidelines on the dosing and administration of polymyxins [44]. The recommendations in this topic are largely consistent with these guidelines.
Intravenous administration — Polymyxins exhibit concentration-dependent killing against bacteria but have almost no post-antibiotic effect. These properties are one of the reasons they are dosed twice daily.
Selection of polymyxin B versus colistin — When a polymyxin is indicated for systemic therapy of an infection, we usually favor polymyxin B over colistin if both are available. The exception is for infections in the urinary tract, for which colistin is preferred. When used to treat multidrug-resistant organisms, polymyxins are often used in combination with other antibiotics. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Approach to treatment'.)
Comparative clinical data are lacking. However, pharmacokinetic data and features suggest that administration of polymyxin B would achieve adequate drug levels more rapidly and reliably than colistin [44,45]. Polymyxin B is administered as the active agent, whereas systemic colistin is administered as a prodrug that has to be converted to the active agent; levels of polymyxin B are not affected by renal function; and even at a given creatinine clearance, wide interindividual variability in colistin levels has been reported. Furthermore, polymyxin B has been associated with lower rates of nephrotoxicity than colistin. (See 'Nephrotoxicity' below.)
Since polymyxin B is extrarenally cleared, urinary concentrations of polymyxin B are low, in contrast to high urinary levels of colistin, which is thus preferred for urinary tract infections.
Polymyxin B — Clinical data informing the optimal polymyxin B dose are overall limited. We generally administer a one-time loading dose of 25,000 units/kg (2.5 mg/kg) [46], followed by a total daily dose of 25,000 units/kg (2.5 mg/kg) divided into two doses of 12,500 units/kg (1.25 mg/kg) every 12 hours. For severely ill patients with infections due to multidrug-resistant organisms (that remain susceptible to polymyxins), we increase the total daily dose to 30,000 units/kg. Ten thousand units are equivalent to 1 mg.
In most modeling scenarios, the exposure to minimum inhibitory concentration (MIC) ratio, area under the concentration-time curve (AUC)/MIC, appears to be the best correlated with bactericidal activity [47].
Although the manufacturer recommends reducing the dose to <15,000 units/kg/day in patients with renal impairment, accumulating pharmacokinetic studies and clinical data suggest that polymyxin B dosing should not be dose adjusted for renal dysfunction or the use of dialysis [44,46,48,49]. We do not dose adjust polymyxin B for impaired renal function; we also do not dose adjust for obesity.
Colistin
Formulations and manufacturer-recommended dosing — Two different formulations of colistin are commercially available for parenteral use, depending on the location. Both contain colistimethate sodium (CMS) powder for reconstitution, but they are formulated differently and have distinct dosing recommendations [3]. One formulation is measured as mg of colistin base activity and the other as international units of CMS; 150 mg colistin base activity is equivalent to approximately 4.5 million international units of CMS (1 mg colistin base activity is equivalent to approximately 30,000 international units of CMS or 2.4 mg CMS) [50].
●In the United States, the colistin formulation is supplied in vials containing 150 mg colistin base activity per vial.
The manufacturer recommended dose for this product is 2.5 to 5 mg/kg per day of colistin base activity divided into two to four equal doses (equivalent to approximately 75,000 to 150,000 international units/kg per day of CMS) for patients with normal renal function [3]. Doses should be reduced in the setting of renal impairment. Optimizing this dose for critically ill patients or multidrug-resistant organisms is discussed below. (See 'Dose optimization' below.)
●In many European countries and elsewhere, the colistin formulation is supplied in vials containing 1 or 2 million international units of CMS.
The manufacturer's recommended dose for this product is 9 million international units of CMS (equivalent to approximately 300 mg colistin base activity) per day in two or three divided doses for patients with normal renal function. A loading dose of 9 million international units may be warranted for critically ill individuals [51]. Doses should be reduced in the setting of renal impairment.
Use of ideal rather than actual body weight has been associated with lower risk of adverse effects [52-54].
Dose optimization — The ideal dose for colistin remains uncertain, and doses on the higher end of the recommended range (eg, a loading dose followed by 4.5 million units of CMS [150 mg colistin base activity] every 12 hours) may be more appropriate for multidrug-resistant organisms or severe illness [55-58], although the limited clinical data are mixed [59-61]. We suggest using an initial loading dose of 9 million international units of CMS (300 mg colistin base).
Dose alterations, such as delivery of a loading dose, have been proposed to achieve therapeutic levels more rapidly because some studies have suggested that, even at high doses, plasma levels of colistin may not initially be high enough to sufficiently exceed the MICs for certain gram-negative organisms [62,63]. Clinical experience with a loading dose of colistin has been generally favorable [59,60,64]. The loading dose concept was tested in 25 critically ill patients with 28 clinical episodes of bacteremia or ventilator-associated pneumonia due to gram-negative bacilli that were sensitive only to colistin and, in some cases, an aminoglycoside [59]. CMS was administered in a loading dose of 9 million units (300 mg colistin base activity) followed by 4.5 million units (150 mg colistin base activity) every 12 hours, with the interval adjusted for renal insufficiency. An aminoglycoside or a carbapenem was coadministered in 14 cases. Clinical cure was obtained in 82 percent. In another study evaluating this same dose of colistin, higher cure rates were reported compared with historical controls who were matched for age and severity and type of infection but received 6 million units CMS (200 mg colistin base activity; 63 versus 41 percent cure rate), and there was no excess nephrotoxicity [60].
In other studies evaluating the rate of nephrotoxicity with higher doses (including a regimen using a loading dose), reversible acute kidney injury occurred in 17 to 44 percent of patients, all of whom were able to complete therapy with dose modifications [59,65]. This incidence range of nephrotoxicity is comparable to historical rates when loading doses were not used. (See 'Nephrotoxicity' below.)
Monitoring — Renal function should be closely monitored during administration of systemic polymyxins. If the patient had decreases in creatinine clearance while on colistin, the dose should be reduced accordingly; dose reduction for polymyxin B is not necessary. The optimal dose modifications for renal function are not well established; an international expert panel has proposed adjustments for particular creatinine clearance levels to achieve particular colistin target levels [44]. Because polymyxins are usually used in cases of severe multidrug-resistant infections when other antibiotic options are limited, the decision to stop a polymyxin in the setting of acute kidney injury should be individualized and weigh the risks of renal failure with those of abbreviated treatment of the infection.
The international expert panel also recommends therapeutic drug monitoring of polymyxins, in part because the therapeutic window between efficacy for multidrug-resistant organisms and toxicity is narrow [44]. The recommended target level is a steady state concentration of 2 mg/mL. However, therapeutic drug monitoring for the polymyxins is not universally available.
Inhaled administration — Both polymyxin B and colistin can be inhaled via nebulizer and have been used in certain settings. Inhaled colistin can be used in the management of patients with cystic fibrosis and chronic infection with P. aeruginosa (see "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Inhaled colistin'). However, the role of inhaled polymyxins in the management of gram-negative pneumonia is controversial, and there are wide variations in clinical practice [44,66]. Given somewhat conflicting data (discussed below) and the lack of clear benefit in randomized trials, we do not routinely use inhaled polymyxins for gram-negative pneumonia, although they are a useful adjunct to systemic antibiotic therapy in select multidrug-resistant cases (particularly when polymyxins are being used for systemic therapy given their poor lung penetration). (See "Pseudomonas aeruginosa pneumonia", section on 'Inhaled antibiotics for selected patients' and "Acinetobacter infection: Treatment and prevention", section on 'Pneumonia' and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Aerosolized antibiotics'.)
Polymyxin B may be more likely to cause airway complications, and so colistin is generally the preferred inhaled polymyxin. We do not use inhaled polymyxin B.
If inhaled colistin is used, it should be administered with caution. There is the concern that its use may select for resistance to colistin in organisms that are already widely resistant to other agents, and its effect on the long-term microbiology of intensive care units is unknown. In addition, the drug breakdown products can cause direct damage to lung tissue, leading to potentially serious and life-threatening side effects. This is particularly true for preparations diluted greater than 24 hours prior to use. If colistin is to be used for nebulized inhalation, it must be mixed immediately prior to administration [67]. The optimal dose of inhaled colistin is uncertain and ranges from 75 to 150 mg colistin base activity (2.25 to 4.5 million international units CMS) twice daily. We typically start at 150 mg twice daily.
Data evaluating the benefit of inhaled colistin in patients with pneumonia are overall mixed, with randomized trials not demonstrating improvements in clinical cure. In a randomized trial of 149 patients with gram-negative ventilator-associated pneumonia, inhaled colistin plus imipenem resulted in faster resolution of respiratory failure and faster microbial eradication than intravenous colistin plus imipenem, but clinical cure rates, intensive care unit stay, and mortality were comparable between the two groups [68]. Another randomized trial compared inhaled colistin with inhaled saline in addition to intravenous antibiotics among 100 patients with ventilator-associated pneumonia caused by either A. baumannii or P. aeruginosa [69]. Although inhaled colistin increased microbial eradication from the respiratory secretions, there was no difference in clinical outcomes, and inhaled colistin increased the rate of bronchospasm. In contrast, in a meta-analysis of nine observational studies, use of nebulized colistin in addition to intravenous colistin for multidrug-resistant hospital-acquired pneumonia was associated with higher cure rates and lower mortality compared with intravenous treatment only [70].
Intrathecal administration — Intrathecal and intraventricular administration of either polymyxin B or colistin have been employed for central nervous system infection due to multidrug-resistant gram-negative organisms [71-73]. Intrathecal polymyxins are administered as an adjunct to systemic antibiotic therapy. Some experts favor colistin over polymyxin B for intrathecal or intraventricular administration because of the limited clinical experience with polymyxin B [44].
The optimal dosing is uncertain given variable doses used in the literature. Guidelines from the Infectious Diseases Society of America (IDSA) recommend [74]:
●Colistin – 10 mg CMS (equivalent to 125,000 international units CMS or 4.2 mg colistin base activity) per day (in one daily dose or two divided doses every 12 hours)
●Polymyxin B – 5 mg (50,000 international units) per day in adults; 2 mg per day children
Intrathecal administration of polymyxins for this indication is discussed in detail elsewhere. (See "Health care-associated meningitis and ventriculitis in adults: Treatment and prognosis", section on 'Intrathecal and intraventricular therapy'.)
ADVERSE REACTIONS — The most important side effect of the intravenous polymyxins is nephrotoxicity; neurotoxicity also occurs, although the frequency and severity are more difficult to define.
Nephrotoxicity — Renal function should be closely monitored during systemic administration of polymyxins, which have been associated with hematuria, proteinuria, and oliguria and acute renal failure due to acute tubular necrosis [4,6,8,75,76]. Colistin should be dose adjusted for renal impairment; renal dose adjustment is likely unnecessary for polymyxin B (see 'Intravenous administration' above). Use of concomitant nephrotoxins should be avoided, if possible [44].
The incidence of reversible renal toxicity with polymyxins ranges from approximately 20 to 60 percent, although this wide range is due at least in part to varying definitions of renal toxicity and broad variations in dosing and dose adjustments with baseline renal dysfunction [1,52,77-82]. Furthermore, it may be difficult to determine the relative contribution of drug toxicity to the development of acute renal failure given the severity of illness, confounding advanced chronic diseases, and the high use of concomitant nephrotoxins in patients receiving polymyxins.
Some observational studies have suggested that colistin is associated with a higher rate of nephrotoxicity than polymyxin B [83-85]. As an example, in a retrospective study of 173 critically ill patients treated with a polymyxin for multidrug-resistant gram-negative bacterial infections, nephrotoxicity occurred in 60 percent of those who received colistin (n = 106) and 42 percent of those who received polymyxin B (n = 67). In most cases, the renal failure was reversible; only one patient developed end stage renal disease. Older age, preexisting renal insufficiency, hypoalbuminemia, and concomitant use of non-steroidal anti-inflammatory drugs are reported risk factors for colistin-induced nephrotoxicity [65,86]. There are limited data on the risk factors for polymyxin B-associated nephrotoxicity.
Intravenous ascorbic acid has been postulated as a potentially useful adjunct to prevent nephrotoxicity because of its anti-oxidative properties. Although it has been associated with a lower likelihood of polymyxin-associated nephrotoxicity [65], a protective effect was not demonstrated in a small randomized trial of 28 patients receiving colistin with or without intravenous ascorbic acid (acute kidney injury in 54 and 60 percent, respectively) [87].
There are minimal data on the renal effects of long-term polymyxin use. In one study of 17 patients who received intravenous colistin for more than four weeks, no serious toxicity was identified [88]. The median serum creatinine value increased by 0.25 mg/dL (22 micromol/L) during treatment compared with baseline but returned close to the baseline at the end of treatment.
Neurotoxicity — Polymyxins have been associated with dizziness, weakness, facial and peripheral paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, which can lead to respiratory failure or apnea. Other neurologic manifestations include psychosis, coma, convulsions, ptosis, diplopia, areflexia, dysphagia, and dysphonia [3,89,90]. Neuromuscular blockade is due to noncompetitive blockade that, unlike aminoglycoside-induced neuromuscular blockade, is not reversed by neostigmine [3].
The incidence of colistin-associated neurotoxicity reported in initial studies was about 7 percent; paresthesias were the main neurotoxic adverse event [91]. Reported toxicity occurred within four days in most patients and was more common in women, but there was no increase in incidence with age. However, in six published series since 1999, only 2 of 230 patients developed suspected colistin neurotoxicity; these manifestations resolved after the drug was discontinued [4-8,75]. Many of these patients were sedated (and sometimes paralyzed), so subtle neurologic abnormalities may have been difficult to detect.
Neurotoxic events related to colistin therapy appear to occur more frequently in patients with cystic fibrosis. In one series, 21 of 31 patients (68 percent) treated with colistin experienced paresthesias, ataxia, or both [39]. All of these apparent colistin-induced neurologic adverse effects, although bothersome, were benign and reversible.
There are limited data on the risk of neurotoxicity with polymyxin B.
Other adverse effects — Hypersensitivity reactions (including rash, pruritus, urticaria, and fever) have been reported in 2 percent of patients [91]. Aerosolization of polymyxins into the airway can be complicated by bronchospasm; bronchodilation prior to administration may be beneficial [92]. Polymyxin B can also cause skin hyperpigmentation [93].
DRUG INTERACTIONS — The polymyxins can interact with a variety of other drugs causing increased toxicity. For specific drug interactions, refer to the drug interactions program included with UpToDate.
SUMMARY AND RECOMMENDATIONS
●Polymyxin B and colistin (polymyxin E) are bactericidal drugs that disrupt the outer cell membrane of gram-negative rods and are primarily used for infections with multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. (See 'Introduction' above and 'Mechanism of action' above.)
●Acquired resistance to polymyxins is uncommon but increasing worldwide. Additionally, certain gram-negative rods are intrinsically resistant. These include Burkholderia cepacia, Serratia marcescens, Moraxella catarrhalis, Proteus spp, Providencia spp, and Morganella morganii. (See 'Spectrum of activity' above.)
●When a polymyxin is used for systemic antibiotic therapy, we suggest polymyxin B rather than colistin (Grade 2C). One exception is for urinary tract infections, for which colistin is preferred. (See 'Selection of polymyxin B versus colistin' above.)
●Polymyxin B is administered in its active form. Dose adjustments for renal impairment appear unnecessary. (See 'Polymyxin B' above.)
●Colistin is formulated as colistimethate sodium for reconstitution for parenteral use. It is measured as grams of colistin base activity in the United States and as international units of colistimethate sodium in Europe. The recommended dosage varies by formulation and manufacturer. When colistin is used, we suggest using an initial loading dose of 9 million international units of colistimethate sodium (300 mg colistin base activity) (Grade 2C). Dose adjustments should be made in the setting of renal dysfunction. (See 'Colistin' above.)
●We suggest not routinely using inhaled polymyxin B or colistin for gram-negative pneumonia (Grade 2C). Inhaled colistin may be a useful adjunctive therapy in select multidrug-resistant cases. If used, inhaled colistin should be administered with caution and must be mixed immediately prior to administration. (See 'Inhaled administration' above and "Acinetobacter infection: Treatment and prevention", section on 'Pneumonia' and "Pseudomonas aeruginosa pneumonia", section on 'Inhaled antibiotics for selected patients'.)
●Penetration of either polymyxin into the cerebrospinal fluid is low when administered intravenously. Intrathecal/intraventricular administration of polymyxins has been employed for central nervous system infection due to multidrug-resistant gram-negative organisms. (See 'Intrathecal administration' above and "Health care-associated meningitis and ventriculitis in adults: Treatment and prognosis", section on 'Intrathecal and intraventricular therapy'.)
●The incidence of renal toxicity ranges from approximately 20 to 60 percent, and renal impairment appears to be reversible. Polymyxin B is associated with a lower risk of nephrotoxicity than colistin. Neurologic toxicity, mainly paresthesias, is also associated with colistin. (See 'Adverse reactions' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
